After cloning of δ, κ, μ receptors, the opioid receptor-like 1 (ORL-1) receptor was cloned as the forth member of the opioid receptor family in 1994, (FEBS Lett. 347, 284-288, 1994, FEBS Lett. 341, 33-38, 1994). Although ORL-1 receptor has about 60% of homology to other opioid receptors, it is clearly different from other opioid receptors, because non-selective opioid receptor antagonist, naloxone, does not bind to the ORL-1 receptor (FEBS Lett. 341, 33-38, 1994). While the ORL-1 receptor is expressed in the periphery organs such as intestine, spleen and so on, it is also widely expressed in the central nervous system, especially in the cortex, hippocampus, hypothalamus, amygdala and spinal cord (Eur. J. Pharmacol. 340, 1-15, 1997, Pharmacol. Rev. 53, 381-415, 2001).
In 1995, the endogenous ligand for the ORL-1 receptor was identified by two different research groups in France and Switzerland at the same time, and named as nociceptin (Nature 377, 532-535, 1995) and orphanin FQ (Science 270, 792-794, 1995), respectively. Nociceptin is a 17-amino acid peptide and 30 plays an important role in the function of central nervous system such as learning, memory, anxiety and stress (Br. J. Pharmacol. 129, 1261-1283, 2000).
Substance abuse and dependence involves any of following classes of substances: alcohol, amphetamine, methamphetamine, cannabis (including marijuana, hashish), cocaine, hallucinogens (including LSD, mescaline, MDMA), nicotine, opioids (including morphine, heroin, codeine, methadone), phencyclidine, ketamine, barbiturates, benzodiazepines (including diazepam, triazolam), inhalants(including toluene, paint thinner).
It is known that the nociceptin, an endogenous agonist for the ORL-1 receptor, is effective in alcohol dependence (Ciccocioppo et al., Psychopharmacology (Berl). 141, 220-224, 1999; Ciccocioppo et al., Psychopharmacology (Berl) 172, 170-178, 2004; Martin-Fardon et al., NeuroReport. 11, 1939-1943, 2000), morphine or cocaine dependence (Sakoori et al., Psychopharmacology (Berl) 172, 129-136, 2004), methamphetamine dependence (Zhao et al., NeuroReport. 14, 2383-2385, 2003).
Furthermore, buprenorphine, a partial agonist at μ opioid and ORL-1 receptors, has been used in clinical for treatment of heroin dependence in numerous countries including the United States, Australia, Sweden and France (Kakko et al., Lancet 361, 662-668, 2003; Ling et al., Addiction 93, 475-486, 1998). Buprenorphine also reduces cocaine use by dually opiate-dependent and cocaine-dependent outpatients (Montoya et al., Clin Pharmacol Ther 75, 34-48, 2004; Schottenfeld et al., Biol Psychiatry 34, 66-74, 1993). More recently, evidence has accumulated in support of its efficacy for treatment of alcohol abuse and dependence (Ciccocioppo et al., Biol Psychiatry 61, 4-12, 2007).
Therefore a small molecule ORL-1 receptor agonist is expected to be effective in the prophylaxis or treatment of for substance abuse and dependence. However, first synthesized ORL-1 receptor agonist Ro64-6198 failed to decrease alcohol drinking, rather increase it at high dose (Economidou et al., Peptides 27, 3299-3306, 2006). This effect probably induced by its residual agonistic activity at μ opioid receptors.
The compound of represented by the formula (I) mentioned in the below, for example, (R)-2-{3-[1-(acenaphthen-1-yl)piperidin-4-yl]-2,3-dihydro-2-oxo-benzimidazol-1-yl}-N-methylacetamide (same as 2-{3-[1-((1R)-acenaphthen-1-yl)piperidin-4-yl]-2,3-dihydro-2-oxo-benzimidazol-1-yl}-N-methylacetamide), is another agonist which possesses highly selective affinity for ORL-1 receptors (WO03/082333).